Examination of the Molecular Pharmacology of Anthracyclines Induced via their Interaction with Iron

蒽环类药物是非常有效的抗癌药物，但由于对心脏有毒性作用，它们的使用受到限制。这被认为是由于这些药物直接结合铁（Fe）。事实上，我们发现蒽环类药物诱导心脏细胞利用铁的方式发生显著变化（dr1 - 3,38; Mol. Pharmacol. 2002, 2003, 2004, 2005）。我们是第一个证明蒽环类药物阻止铁从关键的铁储存蛋白铁蛋白释放。这就阻止了铁在重要过程中的使用。DNA和血红素合成。因此，这种作用可能有助于蒽环类药物对心脏的细胞毒性活性。我们发现，在我的实验室开发的结合铁的新型药物螯合剂在动物身上表现出高活性（DR4），并阻止蒽环类药物介导的铁在铁蛋白中的积累。重要的是，铁螯合剂已被证明可以抑制蒽环类药物介导的心脏毒性。事实上，临床上使用的心脏保护剂ICRF-187实际上是一种铁螯合剂（5,DR6）。然而，ICRF-187在其心脏保护作用方面并不完全成功，并可能导致骨髓抑制（5,DR6）。虽然临床上使用的螯合剂去铁胺（DFO）可以预防蒽环类药物介导的心脏毒性，但其较差的膜通透性限制了其有效性。我们的螯合剂具有高渗透性，克服了DFO （DR4）的缺点。因此，它们对于预防蒽环类药物介导的心脏毒性至关重要。在本研究中，我们将研究蒽环类药物引起的铁代谢变化，并验证新型铁螯合剂可能阻止这些药物的心脏毒性的假设。我们的目标是成为第一个评估制备不能结合铁的蒽环类药物是否可以防止它们的心脏毒性。这将通过制备这些药物的金属配合物来实现，这些金属配合物可以阻止铁的结合。anthracycline-zinc复合物。这些研究对于开发这些非常有用的抗肿瘤药物的低心脏毒性形式非常重要。

Anthracyclines are highly effective anti-cancer drugs, but their use is limited by toxic effects on the heart. This is thought to be due to these drugs directly binding iron (Fe). Indeed, we showed that anthracyclines induced marked changes in the way heart cells utilise Fe (DR1-3, 38; Mol. Pharmacol. 2002, 2003, 2004, 2005). We were the first to show that anthracyclines prevent Fe release from the criticial Fe storage protein ferritin. This prevents the use of Fe for vital processes eg. DNA and haem synthesis. Hence, this effect probably contributes to the cytotoxic activity of anthracyclines on the heart. We showed that novel drugs developed in my lab that bind Fe called chelators show high activity in animals (DR4) and prevent anthracycline-mediated Fe accumulation in ferritin. Importantly, Fe chelators have been shown to inhibit anthracycline-mediated cardiotoxicity. Indeed, the clinically used cardioprotective agent, ICRF-187, is actually an Fe chelator (5, DR6). However, ICRF-187 is not totally successful in terms of its cardioprotective effects and can cause myelosuppression (5, DR6). While the clinically used chelator, desferrioxamine (DFO), can prevent anthracycline-mediated cardiotoxicity, its poor membrane permeability limits its effectiveness. Our chelators are highly permeable and overcome the disadvantages of DFO (DR4). Thus, they are vital to examine for preventing anthracycline-mediated cardiotoxicity. In this proposal we will examine the changes in Fe metabolism induced by anthracyclines and test the hypothesis that novel Fe chelators may prevent the cardiotoxicity of these agents. We also aim to be the first to assess if preparation of anthracyclines which cannot bind iron prevents their cardiotoxicity. This will be done by preparing metal complexes of these drugs which prevent Fe-binding eg. anthracycline-zinc complexes. These studies are important for the development of less cardiotoxic forms of these very useful anti-tumour agents.